Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice.

Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT(-/-))-mice (n = 8-10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT(-/-)-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2(-/-)-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT(-/-)-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2(-/-)-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.

Ultrasound-mediated stimulation of microbubbles after acute myocardial infarction and reperfusion ameliorates left-ventricular remodelling in mice via improvement of borderzone vascularization.

AIMS: Post-infarction remodelling (PIR) determines left-ventricular (LV) function and prognosis after myocardial infarction. The aim of this study was to evaluate transthoracic ultrasound-mediated microbubble stimulation (UMS) as a novel gene- and cell-free therapeutic option after acute myocardial infarction and reperfusion (AMI/R) in mice. METHODS AND RESULTS: For myocardial delivery of UMS, a novel therapeutic ultrasound-system (TIPS, Philips Medical) and commercially available microbubbles (BR1, Bracco Suisse SA) were utilized in a closed-chest mouse model. UMS was performed as myocardial post-conditioning (PC) on day four after 30 minutes of coronary occlusion and reperfusion. LV-morphology, as well as global and regional function were measured repeatedly with reconstructive 3-dimensional echocardiography applying an additional low-dose dobutamine protocol after two weeks. Scar size was quantified by means of histomorphometry. A total of 41 mice were investigated; 17 received PC with UMS. Mean ejection fraction (EF) prior UMS was similar in both groups 53%±10 (w/o UMS) and 53%±14 (UMS, p = 0.5), reflecting comparable myocardial mass at risk 17%±8 (w/o UMS), 16%±13 (UMS, p = 0.5). Two weeks after AMI/R, mice undergoing UMS demonstrated significantly better global LV-function (EF = 53%±7) as compared to the group without PC (EF = 39%±11, p<0.01). The fraction of akinetic myocardial mass was significantly lower among mice undergoing UMS after AMI/R [27%±10 (w/o UMS), 13%±8 (UMS), p<0.001)]. Our experiments showed a fast onset of transient, UMS-induced upregulation of vascular-endothelial and insulin-like growth factor (VEGF-a, IGF-1), as well as caveolin-3 (Cav-3). The mice undergoing PC with UMS after AMI/R showed a significantly lower scar size. In addition, the microvascular density was significantly higher in the borderzone of UMS-treated animals. CONCLUSION: UMS following AMI/R ameliorates PIR in mice via up-regulation of VEGF-a, IGF-1 and Cav-3, and consecutive improvement of myocardial borderzone vascularization.